Novel 18-nor-pregnanic derivative and process for its preparation



United States Patent 3,018,293 NOVEL IS-NOR-PREGNANIC DERIVATIVE ANDPROCESS FOR ITS PREPARATION Gaston Amiard, Noisy-le-Sec, and ReneHeymes, Ro-

mainville, France, assignors to Les Laboratoires Francais deChimiotherapie, Paris, France, a corporation of France No Drawing. FiledDec. 16, 1960, Ser. No. 76,155

Claims priority, application France Dec. 24, 1959 16 Claims. (Cl.260-339) The present invention has as its object a novel 18-nor-pregnanic derivative, A 18 nor pregnene 3,11, ZO-trione, of FormulaI:

as Well as the process for its preparation.

Many very useful compounds of the pregnane series are known which do nothave the angular methyl group in the position (l9-nor-pregnanes) andwhich have an activity superior to that of their 10-methylated homologsof the regular series.

Recently Anliker et al., Helv. Chem. Acta, 1959, page 1071, haveprepared certain compounds lacking the angular methyl group in the 13position, namely, A -l8- nor-pregnene-3,20-dione or l8-nor-progesterone.

The novel compound of the invention, A -18-norpregnene-3,1l,20-trione,lacks the angular methyl group in the 13 position and, due to thell-oxygenated function, is a useful intermediate in the synthesis ofsteroids lacking the angular methyl group in the 13 position of thecortisone series. It is used in the preparation of 18-norcortisone, acompound having cortisonic activity, by a CHaOO-- 3,018,293 PatentedJan. 23, 1962 'ice process of hydroxylation of the A bond to introduce a17u-hydroxy group, dehydrogenation to introduce a A bond andhydroxylation of the 21 carbon atom to introduce a ZI-hydroxy group. Itmay also be used in the synthesis of other lS-nor-steroids.

An object of the present invention is the production of A-18-nor-pregnene-3,1 1,20-trione.

Another object of the present invention is to develop a process which iseconomical and easily used for the preparation of A-18-nor-pregnene-3,11,20-trione.

A further object of the invention is the production of intermediatesuseful in the preparation of A -18-norpregnene-3,11,20-trione, asfollows:

(a) 3d acetoxy 17 methyl l8 nor D homoetiocholane-17-ol-11-one;

(b) 17 methyl 18 nor D homo etiocholane- 3u,l7-diol-11-one, III;

(c) 17 methyl 18 nor D homo etiocholane- 17-ol-3,11-dione, IV;

(0!) 17 chloro 17 methyl 18 nor D homoetiocho1ane-3,11-dione, V;

(e) 17 methyl 18 nor D homo A etiocholene- 3,11-dione and itsS-ethylene-acetal, VI;

(f) 17 methyl 18 nor D homo A etiocholene- 3,11-dione and its3-ethylene-acetal, VIa;

(g) the ozonide of 17-methyl-18nor-D-homo-A -etiocholene-3,11-dione,VII;

(h) 20: acetonyl 4,7 dione 113 formylmethyl4bfimethyl-8afi-perhydrophenanthrene, VIII;

(i 18-nor-pregnane-l65-ol-3,11,20-trione.

These and other objects of the invention will become more apparent asthe description thereof proceeds.

In accordance with the process of the invention, the stages of which areshown in the flow sheet of Table I, A -18-nor-pregnene-3,11,20-trione isobtained starting from 30: acetoxy 18 nor D homo etiocholane-11,17-dione, II. The preparation of the starting material is describedin US. patent application Serial No. 846,- 246, filed October 14, 1959.

TABLE 1-Continued H H OH; o on cihi We (VI) CH3 0 0 CH1 on I o vii viii)H H 0 CH; of Gi I OH -t i o- (VIIIa)3a-acetoxy-l8-nor-D-hon1o-etiocholane 11,17 dione, II, is reacted with amethylmagnesium halide to give-acetoxy-l7rmethy1-18-nor-D-homo-etiocholane-17-01 11- was.

GHQ

drochlorinated to obtain a mixture of 17-methyl-18-nor- D-homo-A-etiocholene-3,1l-dione, VI, and its A -iso mer, Wu. The two compoundsare separated by an acetalization of their ketones in the 3-position andcrystallization of the 3-acetal ofv the A -isomer. After hydrolysis ofthe 3-aceta1, the A -isomer, VI, is subjected to an attack by ozone. Theozonide of l7-methyl-18-nor- D-homo-A -etiocholene-3,1l-dione, V II,formed thereby, is next reduced and the desired2a-acetonyl-4,7-dione-1,8- formylmethyl-4bp-methyl Safiperhydrophenanthrene, VIII, is obtained. This latter compound isselectively cyclized in the presence of an alkaline base to form the A-l8-nor-pregnene-3J1,20-trione, I, of the invention.

According to another characteristic of the invention, the 17-methyl-l8-nor-D-homo-A -etiocho1ene-3, l l-dione compound, VIa, is retransformedinto the chlorinated intermediate (compound V), which avoids discardingthis by-product and allows the production of the latter stages and finalproduct in very high yields.

Within the scope of the above general definition of the invention, theprocess is advantageously executed by the following steps:

(a) The reaction between3u-acetoxy-18-nor-D-homoetiocholane-l1,l7-dione, II, and methylmagnesiumhalide is preferably conducted under anhydrous conditions in inertorganic solvents, such as benzene and tetrahydrofuran, at temperaturesbetween about 5 C. and room temperature using methylmagnesium bromide.

(b) The saponification of 3wacetoxy-l7-methyl-18-nor-D-homo-etiocholane-17-ol-ll-one is conducted in the presence of analkali metal hydroxide and an aqueous lower alkanol, preferably aqueousmethanol and sodium hydroxide at elevated temperatures.

(a) The oxidation of the 3ahydroxyl group of 17-methyl-l8-nor-D-homo-etiocholane-3a,17-diol-1l one is conductedpreferably by an N-bromo-imide or N-brornoamide, such as Nbromosuccinimide, in the presence of an aqueous tert.-lower-alkanol,such as tert.-butanol, at elevated temperature.

(d) The 17-methyl-1S-nor-D-homo-etiocholane-17-01- 3-ll-dione is reactedwith concentrated hydrochloric acid in an inert organic solvent such asether at about room temperature.

-(e) The 17-chloro-17-methyl-1S-nor-D-homo-etiocholane-3,1l-dione isdehydrochlorinated preferably by heating with a mixed lithiumbromide-lithium carbonate in an inert organic solvent such asdimethylformamide at temperatures between about C. and about C.

(1) The 17 methyl-l8-nor-D-homo-A -etiocholene-3, ll-dione is separatedfrom its A -isomer by forming the 3-ethylene acetal of the mixture ofisomers by reacting them in an inert organic solvent with ethyleneglycol in the presence of a small amount of a strong organic acidcatalyst, such as p-toluene sulfonic acid. The A -acetal is separatedfrom its A -isomer by the difiference in solubility in organic solventssuch as methanol or hexane.

(g) The B-ethylene acetal of 17-methyl-18-nor-D- homo-A-etiocholene-3Jl-dione is hydrolyzed by the action of aqueous organicacids, such as aqueous acetic acid, at elevated temperatures.

(h) The mother liquors from the separation step (7) above are evaporatedto dryness and treated according to (d) above to rehydrochlorinate the A-isomer to form 17-chloro-17-methyl-18-nor D homo-etiocholane-3,1ldione,which is then returned to the process.

(i) The 17 -methyl-18-norD-homo-A -etiocholene-3, ll-dione is oxidizedby dissolving in an anhydrou lower alkanol and reacting with ozonizedoxygen at temperatures below C. and preferably at about -75 C.

(j) The ozonide of l7-methyl-18-nor-D-homo-L\ -etiocholene-3,11-dione isreduced by treating the solution of (i) above with hydrogen andthereafter with zinc in the presence of an organic acid such as aceticacid at temperatures between about 75 C. and 0 C. The zinc is removedand a solution of 2ct-acetonyl-4,7-dione-1B-formylmethyl-4bB-methyl-SaB-perhydro phenanthrene in an anhydrous loweralkanol, such as ethanol, is obtained.

(k) The alcoholic solution of the aldehyde compound is cyclized byreacting with an aqueous alkali metal hydroxide solution at temperaturesbetween about 60 and 100, preferably between 85 and 90, and the desiredA -18-nor-pregnene-3,11,20-trione i obtained.

The following examples which are given to illustrate the process of theinvention are non-limitive in character and will make the inventionbetter understood to one skilled in the art. The temperatures are givenin degrees centigrade.

, EXAMPLE Preparation of A -]8-rzor-pregnene-3J1,20-tri0ne, 1

(1) 17-CHLORO-1T-METHYL-lS-NOR-D-HOMO-ETIOCHO- LANE-3,11-DIONE, V

(a) Grignard reacti0n.34.65 gm. of 3-acetoxy-18- nor D-homo-etiocholane11,17-dione, 11, obtained according to the process of US. patentapplication Serial No. 846,246, filed October 14, 1959, were dissolvedin 350 cc. of anhydrous benzene. The steroid solution was slowly added,under an atmosphere of nitrogen and while agitating, to a mixture of 400cc. of benzene and 210 cc. of a solution of 0.95 N-methyl magnesiumbromide in tetrahydrofuran, cooled to 5 C. The reaction mixture was nextagitated at room temperature for 30 minutes, after which it was recooledto 5 C. and hydrolyzed by addition dropwise of 250 cc. of a solution ofammonium chloride. The hydrolyzed reaction mixture was acidified to a pHof 6 to 7 with hydrochloric acid and concentrated in vacuo. The residue,consisting essentially of 3u-acetoxy-17-methyl-18-nor-D- homoetiocholane-l7-ol-11-one, was crystallized from methanol and furnished aproduct melting at about 170 C.

(b) Saponificati0n.-The crystals obtained under (a) above wereintroduced into a mixture of 100 cc. of methanol, 20 cc. of water andcc. of caustic soda and heated under agitation to 50 C. for one hour.The mixture was precipitated then by addition of water and vacuumfiltered. The product thus obtained was washed with aqueous methanol,with ether, with dilute hydrochloric acid and with water. After dryinggm. (that is, 62.5% of theory) of an isomer in the 17 position ofl7-methyl-18-nor Dhomo-etiocholane 3a,17-diol-11- one, 111, wereobtained having a melting point at 220 C. for analysis, the product wasrecrystallized from aqueous alcohol and a sample was obtained whichmelted at 222 C. and had a specific rotation [a] :+21 (c.=l% in alcohol.It was soluble in alcohol, and insoluble in ether, benzene andchloroform. After distillation of the mother liquor from vacuumfiltration, the second isomer in the 17 position of17-methyl-18-nor-D-homoetiocholane-3ot,17-diol-1l-one, III, wasobtained. It was vacuum filtered, washed as previously described and 11gm. (that is, 34.5% of theory) of the product was obtained, which meltedat 180 C.

(c) 0xidation.31 gm. of compound III (mixture of two isomers in the17-position) were introduced in 310 cc. of tert-butanol and 62 cc. ofwater, heated to 60 C. and 36.2 gm. of N-bromo-succinimide were addedthereto, under agitation. The heating was stopped after 3 minutes andthe agitation was continued for several minutes more. The mixture waspoured over a mixture of water and ice containing 20 cc. of sodiumbisulfite and then the decolorized solution was neutralized by sodiumcarbonate. The tert-butanol was evaporated in vacuo and the solution wasextracted several times with ethyl acetate. 6.2 gm. of zinc and 3.2 cc.of acetic acid were added to the ethyl acetate extracts and the solutionwas heated to reflux for 10 minutes. It was then treated with animalcharcoal and filtered with suction. The solution was washed with waterand with a solution of sodium bicarbonate. After drying, 32.5 gmfof17-methyl-18-nor-D- homo-etiocholane-17-ol-3,1l-dione. IV (mixture ofthe two 17-isomers), were recovered which was used without anypurification for the following stage of the synthesis.

While working, in an analogous manner, separately with the two isomersof compound III, the two 17- isomers of compound IV were obtained, onemelting at 200 C. with a specific rotation [a] =-+16 (c.=1% inchloroform) and the other melting at 168 C. with specific rotation [a]=-{-22 (c.=1% in chloroform).

(d) Treatment with hydrochloric acid.32.5 gm. of compound 1V (mixture ofthe two isomers were introduced into 32 cc. of ether, 300 cc. ofconcentrated hydrochloric acid were added and the mixture was agitatedin a closed vessel for 20 minutes. Thereafter water was added, theaqueous mixture was extracted several times with methylene chloride andthe extracts were washed with a saturated solution of sodiumbicarbonate. The extract was dried over magnesium sulfate, treated withanimal charcoal, vacuum filtered, then concentrated by distillationuntil a syrupy consistency was attained. 50 cc. of hexane were added andthe mixture was reheated. An important crystallization was produced bythe heat. The crystallized product was allowed to stand for an hour atroom temperature, vacuum filtered and the product obtained thereby waswashed with a mixture of ether and hexane. After drying 27.7 gm. (thatis, 82% in relation to product 11) of large crystals of a 17-isomer of17- chloro 17 methyl-18-nor-D-homo-etiocholane 3,11- dione, V, wereobtained which melted at 146 C. by recrystallization from a mixture ofmethylene chloride and hexane, a white product was obtained having amelting point of 148 C. and a specific rotation [a] =|17.7 (c.=1% inchloroform). The product was soluble in acetone, chloroform andmethylene chloride; and insoluble in ether, hexane, pentane andpetroleum ether.

Analysis. C H O Cl: Molecular weight=336.89. Calculated: C, 71.29%; H,8.67%; Cl, 10.52%. Found: C, 71.3%; H, 8.7%; Cl, 10.9%.

(2) 17-METHYL-1S-NOR-D-HOMO-A -ETIOCH0LENE-3,11- DIONE, VI

(a) Dehydr0chl0rinati0n.A mixture of 330 cc. of dimethylformamide, 18.4gm. of lithium bromide and 9.25 gm. of lithium carbonate were heated toC., 36.95 gm. of chlorinated compound V (melting point: 146 C.) wereadded thereto and the heating was continued at to C. for 25 minutes.After cooling, water was added and the aqueous suspension was extractedseveral times with chloroform. The chloroform extracts were washed withwater, then dried over magnesium sulfate. The extract was treated withanimal charcoal, vacuum filtered and a chloroform solution of a mixturemethyl-18-nor-D-homo-A -etiocholene-3,11 dione,

of 17-methy1- 18 nor-D-homo-A -etiocholene-3,1l-dione and the A-isomers, VI and VIa, was obtained.

For analysis, the two isomers VI and VIa were isolated by chromatographyover alumina with elution with cyclohexane and with a mixture of benzeneand ether. The A -isomer, VI, melted at 120 C., and had a specificrotation [a] =59.8 (c.=1% in chloroform), and the 'A -isomer, VIa,melted at 120 C. and had a specific rotation [a] =+32.6 (c.=l% inchloroform).

(b) AceIalizatin.lO0 cc. of ethylene glycol and 2 gm. of p-toluenesulfonic acid were added to the chloroform solution of the two isomersVI and VIa, about /3 of the solvent was distilled in 15 minutes and 5gm. of sodium bicarbonate were added to the hot solution. After cooling,water was added and the aqueous solution was re-extracted withchloroform. The extracts, after treatment with animal charcoal, wereconcentrated to dryness in vacuo and the residue crystallized frommethanol. 21 gm. (that is, 54% of theory) of the 3-ethylene acetal of17-methyl-18-nor-Dehomo-A -etiocholene-3,l1 dione, VI, were obtained,which melted at 140 to 142 C.

(c) Hydr0lysis.2l gm. of the 3-ethylene acetal of compound VI wereintroduced into 42 cc. of acetic acid and 21 cc. of water and themixture was heated to 90 C. for 30 minutes. After cooling, water wasadded and the mixture was extracted several times with methylenechloride. The combined extracts were washed with water, with a solutionof sodium bicarbonate and with water, then dried over magnesium sulfate.After treatment with animal charcoal and filtration, the solution wasevaporated to dryness in vacuo and the residue was crystallized fromhexane. 14.66 gm, (that is, 44.7%) of 17- methyl 18 nor-D-homo-A-etiocholene-3,1l-dione, VI, having a melting point of 118 C. wererecovered. The product was soluble in alcohol, ether, benzene, acetoneand chloroform; less soluble in petroleum ether and pentane, andinsoluble in water.

(d) Regeneration of the chlorinated derivative.The methanol motherliquors of the acetal of compound VI obtained under (b) above and thehexane mother liquor of compound VI obtained under (c) above werecombined and concentrated to dryness in vacuo. The residue wasredissolved in cc. of ether, 120 cc. of concentrated hydrochloric acidwas added and the mixture was agitated at room temperature for 45minutes. After the addition of water the aqueous mixture was extractedwith methylene chloride. The extracts were combined, washed with water,with a solution of sodium bicarbonate, then dried,

treated with animal charcoal, filtered and evaporated to dryness.

The residue, taken up in 30 cc. of hexane, was carried to reflux. Thechlorinated compound V, 17-chloro-17- 'weighing1.05 gm. was obtained.

(3) 18-NOR-A -PREGNENE-3,11,20-TRIONE, I

(a) Ozonizatz'on.10 gm. of compound VI were dissolved in 170 cc. ofanhydrous methanol, then, while passing stream of oxygen and whileagitating, the solution was cooled by a mixture of absolute alcohol andsolid carbon dioxide maintained at 75 C., and ozonized oxygen wasbubbled through the solution of compound VI for 3 hours. The resultingsolution of the ozonide of 17- VII, was directly reduced in thefollowing stage of the synthesis.

(b) Reducti0n.-A stream of hydrogen was bubbled through the solution ofthe ozonide VII, obtained according to (a) above, and cooled to 70 C. 20gm, of

powdered zinc were added, then, under agitation, 20 cc.

of acetic acid were added thereto. The temperature was allowed to riseto -5 C. in 30 minutes, then the zinc was removed by vacuum filtration.40 cc. of water were added to the reaction mixture and the solvents weredriven off in vacuo and under an atmosphere of nitrogen until thebeginning of crystallization of zinc acetate. After the addition of 50cc. of methylene chloride and 500 cc. of water containing 5 cc. ofconcentrated hydrochloric acid, the mixture was agitated, decanted andthe aqueous layer was reextracted several times with methylene chloride.The combined organic solutions were washed with a solution of sodiumbicarbonate and with water, then dried over magnesium sulfate. Theorganic solution was concentrated to a small volume, 55 cc. of ethanolwere added and the remaining methylene chloride Was driven oif in vacuo.Thus an alcoholic solution of the aldehyde 2aacetonyl-4,7-dione-l,8-formylmethyl-4bB-methyl-Satiperhydrophenanthrene,VIII, was obtained, which was directly usable for the following stage ofthe synthesis.

By evaporation to dryness in vacuo of this solution and chromatographyover alumina with elution by methanol,18-nor-pregnane-16E-ol-3,11,20-trione, VIIIa, isomer of the aldehydeVIII, having a melting point of 220 C. was obtained.

(0) Cyclz'zation.-The alcoholic solution of the aldehyde VIII wasintroduced, under an atmosphere of nitrogen, into 500 cc. of waterheated to to C. and previously degassed. 10 cc. of normal sodiumhydroxide were added and the heating was continued at 85 to 90 C. forone hour, still under an atmosphere of nitrogen. A slightly oilycrystalline suspension was formed which was cooled to 30 C. Thesuspension was vacuum filtered, the precipitate was washed with waterand dried to recover 9 gm. of raw compound I which was recrystallizedfrom aqueous acetic acid. 6.43 gm. of the pure product, A-18-nor-pregnene-3d1,20-trione, I (that is, 61% in relation to thequantity of compound VI used), were obtained having a melting point of174 to 175 C. and a specific rotation [a] =+97i2 (c=1% in chloroform).The product was obtained in the form of colorless needles, very solublein chloroform, soluble in acetone, slightly soluble in alcohol and etherand insoluble in water and dilute aqueous acids or alkalies.

Analysis.C H O Molecular weight=314.41. Calculated: C, 76.40%; H, 8.34%;O, 15.27%. Found: C, 76.2%; H, 8.3%; O, 16%.

Ultraviolet spectrum, A max. 236 m 5:9500.

While working in an analogous manner with the hydroxy derivative, Villa,compound I was obtained with the same yields.

It will be understood that the invention is not limited to the modes ofoperation described above. It is possible to use as the startingmaterial any other easily saponifiable ester ofl8-nor-D-homo-etiocholane-3a-ol-l1,17-dione or even to use theequivalent techniques known to those skilled in the art withoutdeparting from the spirit of the invention or the scope of the appendedclaims.

We claim:

l. A -18-nor-pregnene-3,11,20-trione.

2. 3a acctoxy-17-methyl-l8-nor-D-homo-etiocholane- 17-01-1 l-one.

3. 17-methyl-18-nor-D-homo-etiocholane-3a,l7-diol-11- one.

4. 17-methyl-1S-nor-D-homo-etiocholane-l7-ol-3,1l-dione.

5. 17-chloro-l7-methyl-18-nor-D-homo-etiocholane-3,- ll-dione.

6. 17-methy1-18-nor-D homo-A -etiocholene-3,1l-dione.

7. The 3-ethylene acetal of 17-methyl-18-nor-D-homo A-etiocholene-3,1l-dione.

8. 17-methyl-18-nor-D homo-A -etiocholene-3,1l-dione.

9. The 3-ethylene acetal of 17-mcthyl-18-nor-D-homo- A-etiocholene-3,1l-dione.

10. The ozonide of 17-methyl-18-nor-D-homo-A -etiocholene-3,l l-dione.

11. 2a-acetony1-4,7-dione-1B-formylmethy1-4bfi-methyl-SaB-perhydrophenanthrene.

12. 18-nor-pregane-16E-ol-3,l1,20-trione.

13. The process of producing A -18-nor-pregnene-3; 11,20-tri0ne whichcomprises the steps of reacting a readily saponifiable organiccarboxylic acid ester of 18- nor-D-homo-etiocholane-3a-ol-l1,17-dionewith a methyl Grignard compound, saponifying the resulting compound,oxidizing the 17-methyl-18-nor-D-homo-etiocholane-3a,- 17-dio1-11-onewith an oxidizing agent selected from the group consisting ofN-bromo-amides and N-bromo-imides in the presence of an aqueoustertiary-lower-alkanol whereby the 3a-hydroxyl group is converted to aketone, reacting the 17-methyl-18-nor-D-homo-etiocholane-17-01-3,1l-dione with concentrated hydrochloric acid, dehydrochlorinating the17-chloro-17-methyl-1S-nor-D-homo-etiocho1ane-3,11-dione whereby amixture of 17-methyl-l8- nor-D-homo-A -etiocholene-3,1l-dione and its Aisomer is obtained, reacting said mixture of A and A" isomers underacetalizing conditions whereby the 3-ketone is acetalized, separatingsaid A -3-acetal from its A -3-acetal isomer, hydrolyzing said A-3-acetal to liberate the 3 ketone, reacting thel7-methyl-18-nor-D-homo-A -etiocholene3,11-dione with ozone at lowtemperatures, reducing the ozonide of 17-methy1-18-nor-D-homo-A-etiocho1ene-3,11dione by the action of hydrogen and thereafter Zinc inthe presence of an organic acid at a temperature between 75 C. and 0 C.,and isolating a lower alkanol solution of2u-acetonyl-4,7-dione-lfl-formylmethyl-4bfi-methyl-SaB-perhydrophenanthrene,cyclizing said perhydrophenanthrene by reacting with an alkaline baseand recovering said A -18-nor-pregnene-3,11,20- trione.

14. The process of claim 13 wherein 3a-acetoxy-18-nor-D-homo-etiocholane-l1,17-dione is utilized as the readilysaponifiable starting compound.

15. The process of claim 13 wherein said 17-methy1- 18-nor-D-homo-A-etiocholene-3,1l-dione is reacted with concentrated hydrochloric acidand the 17-chloro-17- methyl-18-nor-D-homo-etiocholane-3,1l-dione isfurther reacted according to claim 13.

16. The process of claim 13 wherein said lower alkanol solution of2a-acetonyl-4,7-dione-1B-formylmethyl-4bfimethyl-8afl-perhydrophenanthreneis evaporated to drymess, the 18-nor-pregnane-16E-0l-3,11,20-trione isreacted with an alkaline base and A -18-nor-pregnene-3J1,20- trione isrecovered.

UNITED STATES PATENT OFFICE CERTIFICATION OF CORRECTION Patent No. 3 Ol8293 January 23 1962 Gaston'LAmiard et ale It is hereby certified thaterror appears in the above numbered patent requiring correction and thatthe said Letters Patent should read as corrected below.

Column 3, formulas (Villa) and (I) should appear as shown below insteadof as in the patent:

column 4, line 57 for "3uhydr0xyl" read 3 -hydroxyl ==-g line 64, for"3=-lldione" read 3 ll==dione column 5 line 4'2 for N-methyl" read Nmethyl line 71 for "for" read For column 6 line 34 after "isomers"insert a closing parenthesis; line 52, for "by" read By column 7 line 53for "--=etiocholene read etiocholane- --5 column 9 line 5 for"=preganeread pregnane=- line 6 for -"'=ipregnene 91,-" read==pregnene=3 Signed and sealed this 19th day of June 1962,

(SEAL) Attest:

ERNEST W SWIDER DAVID L. LADD Attesting Officer Commissioner of Patents

10. THE OZONIDE OF 17-METHYL-18-NOR-D-HOMO-$16-ETHIOCHOLENE-3,11-DIONE.